Prostate cancer is the most common internal malignancy in men in the United States where it is estimated that 244,000 new cases of prostate cancer will be diagnosed and 42,400 men will die of prostate cancer in 1995. New diagnostic and therapeutic approaches are needed to impact on this steadily increasing health problem. Studies regarding the molecular basis of prostate cancer progression have been impeded due to the extreme tissue heterogeneity of human prostate cancer and the scarcity of useful human prostate cancer cell lines. Through the previous years of funding for this grant, we have developed useful prostate cancer model systems based on the mouse prostate reconstitution (MPR) approach and have used them to study prostate cancer progression in vivo and in vitro. Thus far, we have established that overexpression and accumulation of transforming growth factor-beta1 (TGF-beta1) and loss of p53 function are correlated with local progression and metastasis of prostate cancer. These observations were made initially in our MPR models and subsequently validated in human tissue. More recently, we have determined that loss and/or subversion of TGF-beta1 response pathways likely play important roles in advanced disease. Our hypothesis is that early in the development of prostate cancer, TGF-beta1 inhibits the growth of premalignant/early malignant epithelium. Subsequently, excessive TGF- beta1 promotes the selection of genetic alterations which eliminate/subvert normal TGF-beta1 response pathways and allows intrinsic properties of TGF-beta1 (e.g., immunosuppression) to enhance malignant progression. Preliminary studies using MPR prostate cancer tissues and cell lines selected under conditions of retinoid (4-HPR) therapy, suggest that downregulation of TGF-beta1 expression may be one mechanism of escape from TGF-beta1 growth inhibition. We have also completed a series of studies which address differential response to TGF-beta in primary and metastatic cell lines with regard to several biologically important activities. We have demonstrated in a series of 12 cell lines (6 from primary cancers and 6 from metastatic deposits) that, whereas primary prostate cancer cell lines retain the characteristic growth inhibitory responses to TGF-beta1, those derived from metastases are far less responsive. In contrast, some metastatic cell lines were stimulated by TGF-beta1 to induce activity of MMP-9, a type IV metalloproteinase, while there was little or no such induction in the primary cancer cell lines. Ultimately, loss of TGF-beta1-regulated pathways may converge with loss of p53 function at the level of cell cycle control and lead to metastatic progression. We propose to pursue these concepts through in vitro and in vivo MPR studies and attempt to identify novel genes which play a role in prostate cancer progression.